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Original Article

Exp Neurobiol 2018; 27(6): 489-507

Published online December 28, 2018

© The Korean Society for Brain and Neural Sciences

Insulin-like Growth Factor-1 Receptor Dictates Beneficial Effects of Treadmill Training by Regulating Survival and Migration of Neural Stem Cell Grafts in the Injured Spinal Cord

Dong Hoon Hwang1*, Hee Hwan Park1,3, Hae Young Shin1,4, Yuexian Cui1,5, and Byung Gon Kim1,2,3*

1Department of Brain Science, Ajou University School of Medicine, Suwon 16499, Korea.

2Department of Neurology, Ajou University School of Medicine, Suwon 16499, Korea.

3Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 16499, Korea.

4Logos Biosystems, Anyang 14055, Korea.

5Department of Neurology, Yanbian University Hospital, Yanji 133000, Jilin, China.

Correspondence to: *To whom correspondence should be addressed.
Dong Hoon Hwang, TEL: 82-31-219-4561, FAX: 82-31-219-4444
Byung Gon Kim, TEL: 82-31-219-4495, FAX: 82-31-219-4444

Received: October 26, 2018; Revised: December 13, 2018; Accepted: December 14, 2018

Survival and migration of transplanted neural stem cells (NSCs) are prerequisites for therapeutic benefits in spinal cord injury. We have shown that survival of NSC grafts declines after transplantation into the injured spinal cord, and that combining treadmill training (TMT) enhances NSC survival via insulin-like growth factor-1 (IGF-1). Here, we aimed to obtain genetic evidence that IGF-1 signaling in the transplanted NSCs determines the beneficial effects of TMT. We transplanted NSCs heterozygous (+/−) for Igf1r, the gene encoding IGF-1 receptor, into the mouse spinal cord after injury, with or without combining TMT. We analyzed the influence of genotype and TMT on locomotor recovery and survival and migration of NSC grafts. In vitro experiments were performed to examine the potential roles of IGF-1 signaling in the migratory ability of NSCs. Mice receiving +/− NSC grafts showed impaired locomotor recovery compared with those receiving wild-type (+/+) NSCs. Locomotor improvement by TMT was more pronounced with +/+ grafts. Deficiency of one allele of Igf1r significantly reduced survival and migration of the transplanted NSCs. Although TMT did not significantly influence NSC survival, it substantially enhanced the extent of migration for only +/+ NSCs. Cultured neurospheres exhibited dynamic motility with cytoplasmic protrusions, which was regulated by IGF-1 signaling. IGF-1 signaling in transplanted NSCs may be essential in regulating their survival and migration. Furthermore, TMT may promote NSC graft-mediated locomotor recovery via activation of IGF-1 signaling in transplanted NSCs. Dynamic NSC motility via IGF-1 signaling may be the cellular basis for the TMT-induced enhancement of migration.

Graphical Abstract

Keywords: Spinal cord injury, Neural stem cell, Treadmill training, Insulin-like growth factor-1, Migration, Motility